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Davis calls up a video on his monitor showing the immune system in action. He watches three cells clump together, much like a basketball and two softballs lined up in a row. The largest of the three is a cancerous lymphoma cell. The two smaller cells—one blue, the other red—are components of the immune system scanning the unhealthy cell and communicating with one another about what they are “seeing.”
The time-lapse images follow the two immune cells as their colors swiftly intensify and change to green. This color change is a laboratory-generated display of the internal biochemical changes the immune cells undergo when they recognize the lymphoma cell and signal to other nearby immune cells to mobilize against it. Their murderous business is swift and relentless. Nearly a dozen other cells charge in like a vengeful mob. With their colors intensifying and changing much like the first two cells, they cluster around the lymphoma cell and prepare to kill it.
Davis's team has recorded numerous videos of fluorescently tagged proteins on the surface of the immune system's T lymphocytes—the specialized white blood cells that move through the body with the flow of blood until they bump up against foreign or diseased cells. If the T cell's surface proteins link up with a sufficient number of counterpart proteins on the unhealthy cell, the T cell recognizes it as an enemy. At that point, the immune system swings into attack mode against the invader.
Only with recent advances in visual imaging systems have Davis and other investigators been able to generate these types of live-action videos. Their productions are changing the way scientists think about the immune system.
The imaging systems couple ultra-high-resolution microscopes with lasers (which send out pulses of light that illuminate fluorescently labeled protein probes, even deep within the intact tissues of living animals). These systems, known as multiphoton microscopes, include special video camcorders that produce layers of images at different microscopic depths as well as postproduction software that recomposes the images into three-dimensional videos. Thus equipped, scientists like Davis can watch how the immune system works at the nuts-and-bolts level and observe what happens when it goes awry.
“You can't understand complex, changing natural phenomena with just one snapshot,” says Davis. “We want to see where the molecules are, what they are doing, and how an organism responds to a threat. With video imaging, we can look at the gears turning and what cells do and how they do it.”
Microscopic observation of living cells on a slide (in vitro) or in a living organism, which goes by the general name of “intravital microscopy” (IVM), is not new. It was pioneered by German physiologist Rudolph Wagner in 1839. But the present sophistication of the process and the level of resolution now possible are indeed new, and filled with promise. When Davis and others began to generate videos in the late 1990s, however, some in the field questioned their value. They were seen as a fancy way of showing what scientists already knew through static images.